The protective effects of Cyperus rotundus on behavior and cognitive function in a rat model of hypoxia injury.

CONTEXT: Hypoxia injury (HI) with its long-term neurological complications is one of the leading causes of morbidity and mortality in the world. Currently, the treatment regimens for hypoxia are aimed only at ameliorating the damage without complete cure. The need, therefore, for novel therapeutic drugs to treat HI continues. OBJECTIVE: This study investigates the protective effects of the ethanol extract of Cyperus rotundus L. (Cyperaceae) (EECR), a medicinal plant used in Ayurvedic traditional medicine against sodium nitrite-induced hypoxia in rats. MATERIALS AND METHODS: We have evaluated the protective effect of 200 and 400 mg/kg of EECR against sodium nitrite-induced hypoxia injury in rats by assessing the cognitive functions, motor, and behavioral effects of EECR treatment along with the histological changes in the brain. By comparing the protective effects of standard drugs galantamine, a reversible cholinesterase inhibitor and pyritinol, an antioxidant nootropic drug against sodium nitrite-induced hypoxia in rats, we have tested the protective ability of EECR. RESULTS: EECR at doses of 200 and 400 mg/kg was able to protect against the cognitive impairments, and the locomotor activity and muscular coordination defects, which are affected by sodium nitrite-induced hypoxia injury in rats. CONCLUSION: Based on our results, we suggest that the medicinal herb C. rotundus possesses a protective effect against sodium nitrite-induced hypoxia in rats. Further studies on these protective effects of EECR may help in designing better therapeutic regimes for hypoxia injury.

Pyritinol reduces nociception and oxidative stress in diabetic rats.

The purpose of this study was to assess the antinociceptive and antiallodynic effect of pyritinol as well as its possible mechanism of action in diabetic rats. Streptozotocin (50 mg/kg) injection caused hyperglycemia within 1 week. Formalin-evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Oral acute administration of pyritinol (50-200 mg/kg) dose-dependently reduced flinching behavior in diabetic rats. Moreover, prolonged administration of pyritinol (12.5-50 mg/kg, every 2 days for 2 weeks) reduced formalin-induced nociception. 1H-[1,2,4]-oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, a guanylyl cyclase inhibitor, 2 mg/kg, i.p.), but not naltrexone (a non-selective opioid receptor antagonist, 1 mg/kg, s.c.) or indomethacin (a non-selective cycloxygenase inhibitor, 5 mg/kg, i.p.), blocked the pyritinol-induced antinociception in diabetic rats. Given alone ODQ, naltrexone or indomethacin did not modify formalin-induced nociception in diabetic rats. Oral acute (200 mg/kg) or prolonged (25 mg/kg, every 2 days for 2 weeks) administration of pyritinol significantly reduced streptozotocin-induced changes in free carbonyls, dityrosine, malondialdehyde and advanced oxidative protein products. Four to 8 weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. On this condition, oral administration of pyritinol (50-200 mg/kg) reduced tactile allodynia in diabetic rats. Results indicate that pyritinol is able to reduce formalin-induced nociception and tactile allodynia in streptozotocin-injected rats. In addition, data suggest that activation of guanylyl cyclase and the scavenger properties of pyritinol, but not improvement in glucose levels, play an important role in these effects.

Event-related potentials and psychopharmacology. Cholinergic modulation of P300.

The event-related potential P300 probably reflects the encoding of information into short-term memory. Anatomical structures of the limbic system are involved in this process. Since the same structures are involved in the generation of the event-related potential P300, P300 is thus well suited to assess pharmacological influence on memory functions and cognitive processes, for example, by changing the availability of neurotransmitters like acetylcholine at their respective receptors.

Pyritinol facilitates the recovery of cortical cholinergic deficits caused by nucleus basalis lesions.

The effect of a nootropic, Pyritinol, on the recovery of cortical cholinergic deficits induced by injury of the nucleus basalis has been tested on two groups of unilateral quisqualic acid nbM-lesioned rats. The first group had a 30 nmol lesion producing a cortical cholinergic impairment at 21 days, with a spontaneous recovery at 45 days. The second group had a 50 nmol lesion that produced a deeper cholinergic deficit, which did not recover at 45 days. Pyritinol enhanced the recovery in the 30 nmol group of animals on the 21st day after surgery. The recovery was measured as an increase in the activities of acetylcholinesterase (AChE), choline acetyltransferase (ChAT) and the high affinity choline uptake system, and the histochemical densities of the cortical AChE network and the M2 receptor. Histochemical analysis of the nbM enabled cortical recovery to be related to the number of surviving neurons and also to their hypertrophy and AChE-ChAT hyperactivity. Pyritinol enhanced recovery in 30 nmol lesioned animals but in the other group, with a lower number of surviving neurons and a lower ability of the cells to become hypertrophic, the drug was unable to promote cortical recovery.

Source localization of brain electric field frequency bands during conscious, spontaneous, visual imagery and abstract thought.

This paper addresses the issue of mind-brain correspondence, using a novel way to reduce brain electric field data in the frequency domain to estimates of intracerebral model source locations, and applying this method to brain electric data collected during the 2-s epochs immediately before the randomly solicited reports of spontaneous, conscious, covert experiences from 12 normal volunteers. The mentation reports were classified into visual imagery and abstract thought. The mean locations of the EEG model sources associated with abstract thoughts were generally more anterior and deeper than those of visual imagery, particularly significant for the delta/theta band; the finding was common across subjects. Thus, different brain functional states involving different geometries of activated neural populations exist during conscious, spontaneous, task-free mentations of the visual imagery type and of the abstract thought type.

Differential stimulation of neutrophil functions by pyrithioxine.

The drug pyrithioxine strongly stimulated in vitro migration by rabbit peritoneal neutrophils. The stimulating effect appeared to be chemotactic rather than chemokinetic. Though the drug did not induce exocytosis by itself, it stimulated fMet-Leu-Phe-induced exocytosis. The effect on exocytosis induced by other activators was not statistically significant. No stimulating effect of pyrithioxine on superoxide production was observed, either in the absence or in the presence of activators. For a maximal stimulating effect on migration and exocytosis the presence of extracellular Ca2+ was required. Pyrithioxine caused an increase of cGMP level in neutrophils. The hypothesis is presented that the differential activation of neutrophil functions by pyrithioxine is mediated by cGMP, and that cGMP has a differential importance for the neutrophil functions studied.

Effects of subchronic administration of pyritinol on receptor deficits and phosphatidylinositol metabolism in the brain of the aged mouse.

The effect of pyritinol, a commonly used nootropic drug, on receptor properties and function was investigated in different neuronal systems, possibly associated with age-related decline in brain function. Chronic treatment (15 days) of aged (22 months) female NMRI mice with pyritinol (200 mg/kg) restored the reduced density of N-methyl-D-aspartate receptors in the aged mouse brain. Furthermore, the total number of binding sites of the alpha 2-receptor ([3H]yohimbine binding) decreased after treatment with drug, while the number of high-affinity agonist binding sites ([3H]UK 14304 binding) was not changed. In both systems, receptor affinity was not influenced. The densities of other receptors investigated (muscarinic-cholinergic, benzodiazepine and beta-adrenergic) were not altered by treatment with pyritinol. Additionally, the effect of pyritinol on phosphatidylinositol (PI) metabolism was investigated in dissociated neurones from young and aged mice. Muscarinic-cholinergic induced accumulation of phosphatidylinositol and the inositol phosphate response due to activation of G-protein by fluoride was increased in aged animals, treated with drug. The inositolphosphate response after stimulation with pilocarpine was slightly but not significantly increased. The metabolism of phosphatidylinositol in young animals was not altered by treatment with drug. These results support the hypothesis of a nootropic-mediated restoration of age-related brain deficits. Changes caused by pyritinol may be due to beneficial effects on age-related alterations of the properties of the neuronal membrane.

Effect of pyritinol on EEG and SSEP in comatose patients in the acute phase of intensive care therapy.

The extent and duration of acute disturbances of consciousness depend on the severity and localization of the underlying cerebral dysfunction. The Glasgow Coma Scale (GCS) permits a relevant statement to be made on the course and recovery tendency of functional damage patterns in cerebral, mesencephalic, and brain stem structures. Therapy is directed at exerting a beneficial effect on the disturbed cerebral metabolism by administration of centrally active substances and at utilizing the available reserve plasticity of the brain for any possible recovery of mental performance. The bioavailability and profile of action of pyritinol have been well documented in animal experiments. We have studied the question as to the extent to which the substance influences the depth of coma in patients receiving acute intensive care therapy, and how this can be objectified electrophysiologically in the form of a specific central effect on basal brain structures. In a phase-II pilot study over five days the acute effect of intravenous 60-min. administration of 1,000 mg pyritinol on the depth of coma, the central conduction time (CCT) and the primary complex amplitude (N20/P25) of the SSEP, and on vigilance behavior (spectral edge frequencies and power) was investigated for 90 minutes in each case under intensive-medical steady-state conditions in 10 comatose patients. Because of the differences in the underlying brain damage, the primary depth of coma, age (30-89 years), sex (two female, eight male), as well as previous treatment (surgery, conservative), the significance of the results could not be evaluated by confirmatory statistical analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Detection of nootropic activity indicated by acute inhibition of orientation reaction]. / Vyiavlenie aktivnosti nootropov po pokazateliu ostrogo ugashcheniia orientirovochnoi reaktsii.

Exploratory locomotor activity was studied in the experiments on adult male mice. It was shown that routine nootropic drugs as well as newly synthesized nootropic compounds were able to facilitate the development of inhibition during one registration session. Inhibition may be used for revealing only selective nootropic drugs devoid of sedative and stimulating effects.

Effect of repeated application of nootropic drugs on sleep in rats.

The effects of repeated application of nootropic drugs on the sleep-wake cycle were investigated in rats. Piracetam, meclofenoxate and pyritinol were injected intraperitoneally, 100 mg/kg per day, during a period of 10 days. The sleep-wake cycle was recorded each day between 8 a.m. and 4 p.m. Repeated administration of piracetam and meclofenoxate led to an increase of the paradoxical sleep, a decrease of waking, and a very small increase of slow-wave sleep. Pyritinol, on the other hand, decreased the amount of paradoxical sleep. The paradoxical sleep latency was reduced by piracetam and meclofenoxate and enhanced by pyritinol, respectively. These findings and also previous results show that nootropic drugs have different effects on sleep, especially on paradoxical sleep. The possible relationship between sleep effects and memory effects of nootropic drugs and the usefulness of sleep studies for screening of nootropics are discussed.

Psychopharmacological effects of pyritinol in normal volunteers.

Twelve healthy male volunteers received pyritinol 600 or 1,200 mg or placebo for 3 days according to a randomised, double-blind crossover design. On the 1st and 3rd days of each of the three treatment periods subjects completed a battery of psychological tests including Critical Flicker Fusion (CFFT), Choice Reaction Time (CRT), tests of memory and subjective drug effects at 1, 2, 4 and 6 h after dosing. Significant improvements in CFFT and CRT were found after pyritinol. There were no significant differences on the other tests, however, the observed enhancement in performance could be attributed to the effect of the drug.

Protection of cell proteins against free-radical attack by nootropic drugs: scavenger effect of pyritinol confirmed by electron spin resonance spectroscopy.

The potency of nootropic drugs to protect cell proteins and lipids against free radical attack was studied. In an in vitro system, generating hydroxyl radicals by a Fenton-type reaction, the soluble proteins (bovine serum albumin and cytosol protein from brain) were quickly insolubilized and precipitated. Pyritinol (and tamitinol) exhibited the best protection against insolubilization of protein while centrophenoxine (meclophenoxate) and its dimethylaminoethanol moiety were less effective, piracetam (and oxiracetam) being without effect. The lipid peroxidation induced by free radicals from cyclic redox reactions of iron-ascorbate was not influenced by pyritinol, indicating the selectivity of its scavenger action. The efficient scavenging of hydroxyl radicals by pyritinol was confirmed by electron spin resonance spectroscopy measurement of hydroxyl radicals entrapped by spin trap. Millimolar concentrations of pyritinol competitively decreased the formation of spin adducts. The results suggest that the protective effect of pyritinol against free-radical induced derangement of cell proteins may be an important part of its antirheumatic, as well as nootropic, action.

The influence of alpha-tocopherol and pyritinol on oxidative DNA damage and lipid peroxidation in human lymphocytes.

Unscheduled DNA synthesis (UDS) and lipid peroxidation (LPO) were measured in human peripheral lymphocytes from healthy volunteers. These processes were induced by the catalytic system Fe2+-sodium ascorbate. The degree of induced LPO was measured spectrophotometrically by the thiobarbituric acid assay. UDS was detected by scintillometric measurement of the incorporation of 3H-thymidine into DNA. The protective action by fat-soluble vitamin E (D,L-alpha-tocopherol) and the artificial antioxidant pyritinol on UDS and LPO was also investigated. The system Fe2+ (2 mumole/l)-sodium ascorbate (30 mumole/l) increased the LPO level in healthy volunteers approximately 2.5 times and the incorporation of 3H-thymidine by 60-70%. alpha-Tocopherol (0.2 mmole/l) very efficiently suppressed LPO processes (p less than 0.01) and the oxidative damage of DNA measured as UDS was also significantly diminished (p less than 0.05). Pyritinol had no effect on LPO and UDS under our experimental conditions.

[Stimulation of prenatal development in laboratory animals by nootropics]. / Stimulation der pränatalen Entwicklung bei Laboratoriumstieren durch Nootropika.

Described in this paper is the use of nootropics for stimulation of prenatal development of laboratory animals. Investigations, in that context, led to the discovery of so far unknown and unexpected properties of this group of medicaments. Foetal weight gain, reduction of teratogenicity, and decrease in implantation loss proved to be some of them.

Effect of pyritinol on the dopaminergic system and behavioural outcome in an animal model of mild chronic postnatal hypoxia.

Rats after mild chronic postnatal hypoxia always show late sequelae of behaviour and long-term alterations of neurotransmitter release from striatal slices. It was to test preventive or therapeutic actions of drugs using the model of mild chronic postnatal hypoxia of the rat. Pyritinol prevented the learning deficit due to hypoxia and decreases the potassium stimulated DA release from striatal slices. The experiments underline the high plasticity of the CNS during the neonatal period and stress the necessity of early therapy of perinatal brain damage.

Testing drug effects against hypoxic damage of cultured neurons during long-term recovery.

Cultured neurons of chick cerebral embryo hemispheres were used to study drug effects against neuronal damage caused by hypoxia during long-term recovery. Sodium cyanide (NaCN, 1 mmol/l) induces hypoxia-like conditions by inhibiting oxydative phosphorylation. The sensitivity of the cultured neurons against this type of hypoxia was determined after 3, 4, 5 and 6 days of cultivation followed by 4, 3, 2 days and 1 day of recovery, respectively. The ATP level and the viability of cells as well as the total cell number and the protein content of the cultures were used to characterize the extent of posthypoxic neuronal damage. A hypoxic period of 30 min after 4 days of cultivation followed by 3 days of recovery seemed to be appropriate for determining protective drug effects. The drug effects obtained were comparable to those from in vivo models of cerebral ischemia or hypoxia. The results suggest that cultured neurons exposed to hypoxia and to long-term recovery could be suitable for studying post-hypoxic neuronal damage as well as neuroprotective drug effects.